A Key Role for Matrix Metalloproteinases and Neutral Sphingomyelinase-2 in Transplant Vasculopathy Triggered by Anti-HLA Antibody

  • Sylvain Galvani
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Magali Trayssac
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Nathalie Augé
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Jean-Claude Thiers
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Denis Calise
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Hans-Willi Krell
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Federico Sallusto
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Nassim Kamar
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Lionel Rostaing
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Mogens Thomsen
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Anne Nègre-Salvayre
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).
  • Robert Salvayre
    From INSERM UMR-1048, Toulouse, France (S.G., M. Trayssac, N.A., J.T., D.C., M. Thomsen, A.N.-S., R.S.); Faculty of Medicine, Department of Biochemistry, University of Toulouse, Toulouse, France (S.G., M. Trayssac, J.T., N.K., L.R., R.S.); Roche Diagnostics GmbH, Penzberg, Germany (H.K.); CHU Rangueil, Department of Nephrology, Toulouse, France (F.S., N.K., L.R.); and INSERM UMR-1027, Toulouse, France (M. Thomsen).

抄録

<jats:sec><jats:title>Background—</jats:title><jats:p>Outcomes for organ transplantation are constantly improving because of advances in organ preservation, surgical techniques, immune clinical monitoring, and immunosuppressive treatment preventing acute transplant rejection. However, chronic rejection including transplant vasculopathy still limits long-term patient survival. Transplant vasculopathy is characterized by progressive neointimal hyperplasia leading to arterial stenosis and ischemic failure of the allograft. This work sought to decipher the manner in which the humoral immune response, mimicked by W6/32 anti-HLA antibody, contributes to transplant vasculopathy.</jats:p></jats:sec><jats:sec><jats:title>Methods and Results—</jats:title><jats:p>Studies were performed in vitro on cultured human smooth muscle cells, ex vivo on human arterial segments, and in vivo in a model consisting of human arterial segments grafted into severe combined immunodeficiency/beige mice injected weekly with anti-HLA antibodies. We report that anti-HLA antibodies are mitogenic for smooth muscle cells through a signaling mechanism implicating matrix metalloproteinases (MMPs) (membrane type 1 MMP and MMP2) and neutral sphingomyelinase-2. This mitogenic signaling and subsequent DNA synthesis are blocked in smooth muscle cells silenced for MMP2 or for neutral sphingomyelinase-2 by small interfering RNAs, in smooth muscle cells transfected with a vector coding for a dominant-negative form of membrane type 1 MMP, and after treatment by pharmacological inhibitors of MMPs (Ro28-2653) or neutral sphingomyelinase-2 (GW4869). In vivo, Ro28-2653 and GW4869 reduced the intimal thickening induced by anti-HLA antibodies in human mesenteric arteries grafted into severe combined immunodeficiency/beige mice.</jats:p></jats:sec><jats:sec><jats:title>Conclusions—</jats:title><jats:p>These data highlight a crucial role for MMP2 and neutral sphingomyelinase-2 in vasculopathy triggered by a humoral immune response and open new perspectives for preventing transplant vasculopathy with the use of MMP and neutral sphingomyelinase inhibitors, in addition to conventional immunosuppression.</jats:p></jats:sec>

収録刊行物

  • Circulation

    Circulation 124 (24), 2725-2734, 2011-12-13

    Ovid Technologies (Wolters Kluwer Health)

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